tbuckley/cabot-search huggingface dataset:
PB1739: ADVERSE EFFECTS OF ASPARAGINASE IN THE TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Wafa Chenbah, Nesrine Ben Sayed, Haifa Regaieg, Monia Guermazi, Yosra Ben Youssef, Emna Bouslama, Kmira Zahra, Abderrahim Khelif
Journal: HemaSphere (2023)

Topic: 2. Acute lymphoblastic leukemia - Clinical Background: Asparaginase is an essential constituent of the treatment of Acute Lymphoblastic Leukemia (ALL). Its use has improved the efficacy of induction chemotherapy. However there is a risk of associated adverse events that may jeopardize the outcomes. Aims: The Objective of this retrospective study is to describe the asparaginase toxicity in the treatment of ALL. Methods: We analyzed, in collaboration with the regional pharmacovigilance center of Sousse, the medical records of 249 ALL patients treated at the hematology department of Farhat Hached Hospital with Asparaginase containing regimens from Jan 2008 to Dec 2022. Drug causality was assessed using the Naranjo score. We retained the side effects labeled as “probable” and “definite”. Results: The average age was 15 years (1-66 years) with a gender-ratio (M/ F) 1.14.Over one quarter (25,3%) of the study population experienced adverse effects from Asparaginase. In total, 67 adverse events were observed: 41 (16.4%) experienced hypersensitivity reactions, 11 (4.4%) thrombotic accidents, 7 (2.8%) hepatic damage, 6 (2.4%) pancreatic damage and 2 (0.8%) metabolic type of hyperglycemia. Fifty two percent of adverse reactions occurred during induction. Four patients presented with multisystem involvement. We found a statistically significant relationship between the occurrence of cerebral thrombosis, hypersensitivity and age under 18 years (p = 0.01 and p = 0.02, respectively). We also found a statistically significant relationship between hyperglycemia and pancreatitis; and disease relapse (p <0.01) Summary/Conclusion: Hypersensitivity and cerebral thrombosis following Asparaginase administration have a higher risk of occurrence under age 18. This warrants supplementary precaution. Keywords: Acute lymphoblastic leukemia, Side effects
P1564: THE ROLE OF THE NECROPTOSIS IN SEVERE MALARIAL ANEMIA: INSIGHTS FROM RIPK1 ABLATION MODELS
Authors: Ana Pêgo, Illyane Lima, Raffaella Gozzelino
Journal: HemaSphere (2023)

Topic: 30. Infections in hematology (incl. supportive care/therapy) Background: Severe malarial anemia (SMA) is a complication developed during Plasmodium infection. It is often associated with increased rates of malaria-related morbidity and mortality, especially in children and pregnant women. Ineffective erythropoiesis and increased red blood cell destruction are the main features of this disease. Cell death pathways have been proposed as a possible contributor for the hallmarks of the disease, in particularly, the necroptotic pathway. Aims: To better understand its involvement in disease severity, wild-type mice were infected with Plasmodium chabaudi chabaudi (Pcc) and the role of the receptor-interacting protein kinase 1 (RIPK1) during SMA was investigated. Methods: By using RIPK1 knock-in mice, carrying a mutation mimicking serine 25 phosphorylation (Ripk1S25D/S25D), which abrogates RIPK1 kinase activity, we assessed the role of this gene during erythropoiesis, by flow cytometry techniques. Results: One allele mutation is already sufficient to observe a significant decrease in erythroid cells production, under physiologic and pathologic conditions, when compared to wild type. Upon infection, our data show that splenic stress erythropoiesis is increased in infected Ripk1S25D-/+, indicating an important compensatory role of RIPK1, in response to bone marrow erythroid cell depletion. An elevated immune response activation was found in Pcc-induced Ripk1S25-/+ and Ripk1S25-/-, when compared to wild type, in terms of activated immune cell counts and pro-inflammatory markers, like CXCL1, TNF-α, and IL-12p40. This effect was accompanied by an increased disruption of iron homeostasis into affected tissues, when compared to Pcc-induced wild type animals. Summary/Conclusion: Hence, our results suggest RIPK1 as a potential target to ameliorate the severity induced by SMA and regulate iron metabolism. Keywords: Malaria, Iron metabolism, Inflammation, Infection
S243: LACTATE PRODUCED BY T CELLS DURING AGVHD PROMOTES SECOND SIGNAL GENERATION FOR T CELL ACTIVATION THROUGH HISTONE MODIFICATION
Authors: Hengwei Wu, Xin Jin, Fei Gao, He Huang, Yanmin Zhao
Journal: HemaSphere (2023)

Background: aGVHD is marked by T cell pro-inflammatory activation, which involves a shift from oxidative phosphorylation to glycolysis. This metabolic transition results in the production of lactate, a by-product that can induce histone lactylation and alter gene transcription. Aims: To investigate the influence of histone lactylation on T cells in the context of aGVHD. Methods: We established a murine model of aGVHD and isolated CD3+ T cells on Day 14. Histone lactylation was confirmed through Western blot analysis. To gain a comprehensive understanding of histone lactylation in T cells, we employed the cleavage under targets and tagmentation (CUT&Tag) technique, which specifically targets the H4K12 site. This allowed us to generate a panoramic view of histone lactylation in T cells. Results: Activated T cells exhibited increased intercellular lactate and increase Pan-lysine lactylation (Pan-Kla) (A). We observed an increase in histone lactylation of T cells in aGVHD mice. Western blot analysis showed elevated levels of Pan-Kla and specific histone sites, including H4K12la, H3K14la and H3K18la, compared to Bone Marrow-T cell Depletion (BM-TCD) mice (B). Using CUT&Tag with H4K12la-specific antibodies and deepTools analysis, we identified significant enrichment of H4K12la peaks in T cells of aGVHD mice compared to BM-TCD mice (C). The called peaks identified candidate genomic loci at T cell costimulatory genes, including Cd28, Icos, and Tnfrsf9. Elevated levels of H4K12la were observed at promoters of these genes, suggesting that lactylation may positively regulate their expression and promote the formation of a second signal for T cell activation. To confirm the specific impact of lactylation on the transcription of these costimulatory genes, we employed the lactylation writer p300 inhibitor, A485, to reduce histone lactylation, and the lactate dehydrogenase inhibitor (LDHi), to decrease lactate production. Inhibition of p300 in vitro reduced T cell activation and differentiation, resulting in a quiescent state rather than effector or memory phenotypes (D). Treatment with A485 significantly reduced ICOS and CD25 expression on both CD4+ and CD8+ T cells, similar to the effects of LDHi on T cell activation (E). Summary/Conclusion: In this study, we report an increase in histone lactylation in T cells during aGVHD. Using CUT&Tag technique, we demonstrate the positive regulatory role of H4K12la in the second signal of T cell activation. These findings provide novel insights into the roles of lactate and glycolysis, improving our understanding of immunity in the context of aGVHD.Keywords: Allogeneic hematopoietic stem cell transplant, Graft-versus-host disease (GVHD), Allogeneic
P741: PATIENTS’ PERSPECTIVES ON ORAL DECITABINE AND CEDAZURIDINE FOR THE TREATMENT OF MYELODYSPLASTIC SYNDROMES
Authors: Amer M. Zeidan, Kate Perepezko, Tehseen Salimi, Terri Washington, Robert Epstein
Journal: HemaSphere (2023)

Background: Hypomethylating agents (HMAs) are guideline-recommended treatment for higher-risk myelodysplastic syndromes (MDS). However, a prior patient survey (Zeidan, 2022) reported challenges with intravenous/subcutaneous (IV/SC) HMA therapy, including pain related to treatment administration and interference with daily activities. Aims: This study evaluated the perspectives of MDS patients receiving oral decitabine and cedazuridine (DEC-C), an alternative to IV/SC HMAs. Methods: An online survey was conducted among adult patients with MDS in the US (11/2022─12/2022) who had filled a prescription for DEC-C between 2021–2022. Results: A total of 150 patients completed the survey (61% aged ≥60 years, 63% male). Of these, 123 (82%) were still receiving DEC-C and 27 (18%) had stopped treatment. Half (50%) of patients had received DEC-C for ≥6 months. The majority reported that treatment was convenient (83%) and that they were satisfied with treatment (86%). Most patients also reported very little/no interference with regular daily activities (82%), social activities (79%), and productivity (78%). When queried about negative impacts on quality-of-life, treatment side-effects were the most commonly reported (30% of respondents). Among patients who had previously received IV/SC HMAs (n=91), most agreed that DEC-C interfered less with daily life (91%) and had experienced improvement in quality-of-life (85%) compared with previous treatment; 91% reported that DEC-C reduced the number of times they needed to travel to a healthcare facility (Figure). Summary/Conclusion: Survey results suggest very little/no impact on regular daily activities and improved quality-of-life with oral DEC-C relative to IV/SC HMAs, highlighting the potential for DEC-C to reduce the treatment burden associated with parenteral HMA therapy.Keywords: Oral, Hypomethylating agents, Myelodysplastic syndrome, Quality of life
P328: CHARACTERIZATION OF A DUX4-R INHIBITOR AS A POSSIBLE TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: Mara Salomè, Daniele Campolungo, Valeria Runfola, Maria Pannese, Michela Carlet, Claudia Caronni, Roberto Giambruno, Chiara Ghirardi, Irmela Jeremias, Davide Gabellini
Journal: HemaSphere (2023)

Background: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the major cause of cancer-related death before the age of 20. In up to 10% of cases, the disease is caused by translocation of the double homeobox 4 (DUX4) transcription factor to the immunoglobulin heavy chain (IGH) locus, giving rise to rearranged (DUX4-r) versions, maintaining the DNA binding domain (dbd) of WT DUX4 but with variable C-termini. DUX4-r has transforming ability in cellular and animal models and it is necessary for leukemia maintenance. Through proteomics, we identified a potential DUX4-r inhibitor (iDr) for its ability to bind directly to the DUX4-r DNA-binding domain (dbd). Aims: The aim of this study is to test the inhibitory potential of iDr in cellular and animal models of DUX4-r leukemia. Methods: iDr or its fragments were delivered by means of lentiviral vectors in human leukemia cell lines to test the effects on cell adhesion, proliferation and target gene expression. Overexpression of iDr in human B-ALL patient derived xenograft cells was used to test iDr-dependent effect on PDX cells expansion and leukemia latency in mice. Human markers and GFP expression were monitored over time in peripheral blood (PB) to assess disease progression. Results: We found that iDr and its fragments retaining DUX4-r binding decrease DUX4-r dependent transactivation and targets expression. Intriguingly, iDr selectively blunts DUX4-r leukemia cell adhesion and proliferation, with negligent effect on cells not expressing DUX4-r. In vivo, iDr significantly downregulates DUX4-r targets and reduces leukemia burden delaying the expansion of DUX4-r PDX cells. We are currently testing the effects of a smaller fragment of iDr which retains the inhibitory capacity of DUX4-r. Summary/Conclusion: Delivery of iDr and its fragments retaining DUX4-r binding reduce DUX4-r target gene expression selectively blunting proliferation of cells expressing DUX4-r. Pre-clinical validation of iDr fragments could identify effective therapeutic approaches for the treatment of DUX4-r B-ALL patients. Keywords: Lentiviral transduction, B cell acute lymphoblastic leukemia, Xenotransplantation, ALL
P644: IBRUTINIB DOSE MODIFICATIONS FOR MANAGEMENT OF CARDIAC ADVERSE EVENTS IN PATIENTS WITH B-CELL MALIGNANCIES: POOLED ANALYSIS OF 10 CLINICAL TRIALS
Authors: Deborah Stephens, Jennifer R. Brown, Shuo MA, Michael Wang, Carol Moreno, Tadeusz Robak, Don Stevens, Shane Lee, Chadi Saifan, Emily Hsu, Sima Patel, Jan Burger
Journal: HemaSphere (2023)

Background: Continuous therapy with once-daily ibrutinib is associated with long-term progression-free survival (PFS) in patients with B-cell malignancies. Dose reduction is a potential adverse event (AE) management approach that may optimize treatment outcomes. Aims: We evaluated outcomes with dose reductions in ibrutinib-treated patients with cardiac AEs. Methods: Data were pooled for ibrutinib-treated patients from 10 studies of CLL (n=781), mantle cell lymphoma (MCL; n=250), marginal zone lymphoma (MZL; n=63) or Waldenström macroglobulinemia (WM; n=169). Cardiac AEs, initial and recurrent, were identified by preferred terms within the cardiac disorders system organ class. Recurrence was defined as an AE of same or worse grade and was measured up to 30 days after last dose of ibrutinib or start of next-line therapy, whichever occurred earlier. Results: Overall, 234/1263 patients (19%) had cardiac AEs of any grade. Twelve patients were excluded from the analysis: 9 who had a dose reduction prior to a cardiac AE (0.7%) and 3 who had a fatal cardiac AE with no prior cardiac AE (0.2%). Of the remaining 222 patients with grade 1-4 cardiac AEs, 22 (10%) had ibrutinib dose reduction to 420 mg (n=3), 280 mg (n=10), or 140 mg (n=9) after a cardiac AE. These patients (n=22) tended to be older (≥75 years: 45% vs 29%), less heavily pretreated (≥1 prior therapy: 45% vs 73%), and with a lower ibrutinib discontinuation rate (23% vs 48%) than those without dose reduction (n=200). Recurrence of the same cardiac AEs at the same or worse severity was less frequent in patients with dose reductions, both overall (14% vs 18%) and as serious AEs (5% vs 10%). No patient died due to cardiac AE recurrence. Among patients with cardiac AEs who started with the 420 mg ibrutinib dose (177/222; excludes 45 patients with MCL or MZL who per label start with 560 mg dose), no cardiac AE recurred at same or worse severity in the subset with dose reductions (Table). PFS was not negatively impacted by dose reduction, both overall (n=22; median PFS not reached [NR], 24-mo PFS: 91%), and in those who started with the 420 mg dose (n=18; median PFS NR; 24-mo PFS, 94%). Summary/Conclusion: Dose reduction for cardiac AEs may enable patients to continue to benefit from long-term ibrutinib and mitigate the risk of cardiac AE recurrence or worsening.Keywords: Chronic lymphocytic leukemia, Safety, ibrutinib
S311: EFFICACY OF INTRAVENOUS IRON TREATMENT FOR CANCER PATIENT WITH ANEMIA, RANDOMIZED CONTROLLED STUDY
Authors: Jun Ho Jang, Kyunghwa Park, Sung Yong Oh, Hyun Woo Lee, Hyeon-Seok Eom
Journal: HemaSphere (2023)

Topic: 29. Iron metabolism, deficiency and overload Background: Cancer/Chemotherapy Induced Anemia(CIA) is one of common and serious cancer or chemotherapy related complications. Previous studies have demonstrated benefits of intravenous(IV) iron treating CIA in combination with ESA or alone, but there are limited randomized trials. Aims: This study is aimed to assess the efficacy of an IV iron for the treatment of CIA compared to standard of care. Methods: This randomized controlled study prospectively enrolled CIA patients with hemoglobin(Hb) 8.0~ 10.5 g/dL or a decreased Hb >2g/dL during chemo and/or targeted therapy from Dec 2019 to Apr 2022 in 5 centers. Patients were randomized as 2: 1 to active arm(ferric carboxymaltose, Ferinject) vs controlled arm. Active arm patients had Ferinject 1,000 mg at once, and controlled arm had standard of care for CIA (e.g., oral iron, ESA and transfusion). Primary endpoint was the number of Hb responders defined as patients with increased Hb ≥ 1.0 g/dL from baseline, or reached to Hb ≥ 11.0 g/dL within 8-week observation period. Trial registration: NCT04187716 Results: 340 patients were randomized to Ferinject arm(228), and to controlled arm(112). Mean age was 60.8 ± 13.2 years, and 58.9% were women. Major cancer types were gastric(n=106, 32%), lung(n = 87, 26%), breast (n = 74, 22%). Palliative and neoadjuvant treatment were 75% and 15% respectively. Hb responders at 8 weeks are 86 patients in Ferinject arm vs 28 patients in controlled arm among 165 vs 85 patients who completed the study(52.1% vs 32.9%, p=0.0039). The mean Hb increase at 8 weeks from the baseline is also significantly differed: 1.04± 1.61 g/dL in Ferinject arm vs 0.42± 1.36 g/dL (p=0.0027) in controlled arm. Spearman rank correlations demonstrated a negative association between baseline hepcidin and change from baseline Hb concentrations in the Ferinject group (r=-0.32; p = 0.0031). Although it was not a strong correlation, it showed a statistically significant value. Baseline values of hepcidin (p=0.0489), sTfR (p=0.0431) and TSAT (p=0.0019) were significantly different between the responder and non-responder groups in Ferinject arm. Summary/Conclusion: Intravenous ferric carboxymaltose (1,000 mg) monotherapy significantly results more Hb responders, and significantly increases mean Hb levels without treatment related serious adverse events in CIA patients compared to standard of care. Further study is needed to define the predictive serum hepcidin response threshold for IV iron. Keywords: Iron, Chemotherapy-induced anemia
P1455: THROMBOEMBOLIC EVENTS IN SPLENECTOMISED VERSUS NON-SPLENECTOMISED THALASSEMIA PATIENTS: A META-ANALYSIS OF OBSERVATIONAL STUDIES
Authors: Tsampika Vasileia Kalamara, Konstantinos Dodos, Efthymia Vlachaki
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: Thalassemia comprises a heterogenous group of genetic disorders characterised by reduced or absent globin synthesis. Clinical phenotypes include thalassemia minor, intermediate and major, ranging from asymptomatic disorder to severe transfusion requirements. Despite the improvement in therapeutic management in the era of new agents such as luspatercept, splenectomy remains an important treatment option, especially in low income countries. However, splenectomy has been linked to thromboembolic complications in several studies, a factor that increases morbidity and mortality in these patients. Aims: In this meta-analysis we sought to provide pooled effect estimates regarding the impact of splenectomy on thrombosis, by retrieving relevant, available studies, in order to quantify the possible risk for thrombosis that arises from this procedure. Methods: We searched Pubmed, Cochrane library and grey literature from inception to the 20th of February 2023 for studies reporting on major and intermediate thalassemia patients who had undergone splenectomy and their matched controls who were not splenectomised. We recorded the incidence of thromboembolic complications in splenectomised versus non-splenectomised patients. Results were pooled with the use of a random-effects model. Odds ratios (OR) and 95% confidence intervals (CI) were calculated. RevMan 5.4 software was used for the statistical analysis and presentation of the results. Results: We collected data from six observational studies, 3 of which were prospective, in a total of 923 patients, 482 of whom were splenectomised. The random effects model meta-analysis revealed that the incidence of thrombosis was significantly higher in thalassemic patients with splenectomy compared to those without splenectomy [OR=7.59, CI (2.45-23.49)]. The heterogeneity of the included studies was low (I2=0). The test for overall effect confirmed statistical significance (P=0.0004). Venous thrombosis constituted the vast majority of thromboembolic events, the most common of which appeared to be portal vein thrombosis (41%). Summary/Conclusion: The present meta-analysis confirms a strong correlation between splenectomy and thrombotic events in patients with thalassemia major and intermediate. Splenectomised thalassemic patients presented with thrombosis 7.59 times more often than non-splenectomised patients. This result may have clinical implications and assist evidence-based therapeutic decisions and thromboprophylaxis management in the future.Keywords: Meta-analysis, Thalassemia, Thromboembolic events, Splenectomy
PB1904: CAN „CUP LIKE“ NUCLEAR CYTOMORPHOLOGY PREDICT NUCLEOPHOSMIN MUTATED STATUS IN PATIENTS WITH ACUTE MYELOID LEUKEMIA?
Authors: Ljubomir Jakovic, Vesna Djordjevic, Nada Kraguljac Kurtovic, Sandra Bizic, Jelica Jovanovic, Vesna Knezevic, Tijana Dragovic, Marijana Virijevic, Zlatko Pravdic, Andrija Bogdanovic
Journal: HemaSphere (2023)

Topic: 4. Acute myeloid leukemia - Clinical Background: It is known that blasts in acute myeloid leukemia with mutated nucleophosmin gene (NPM1) may have distinct morphological appearance described as „cup like“ nuclei. Aims: To evaluate frequency and predictive value of typical nuclear morphology at diagnosis in AML cases diagnosed at single academic center between 2019 to 2022, enabling early identification of NPM1 status. Methods: Presence and frequency of „cup like“ nuclear morphology was evaluated on 500 blast cells by two independent observers (LJ, AB). Predictive values were calculated with MedCalc® software towards NPM1 mutated status determined by RQ-PCR (Qiagen®) in patients with normal karyotype. Results: Our main group included 265 consequtive AML cases. In 52 patients (19.6%) NPM1 mutation was confirmed. “Cup like” morphology was revealed at diagnosis in 19 pts (36.5%), with median 26% of nuclei (range 11-54%). Wrong call was present in 3 of 213 pts. Statistical evaluation shown that early identification of “cup like” nuclei suggesting NPM1 status has accuracy of 86.4%, specificity of 98.6%, sensitivity of 36.5%; positive and negative predictive values are 86.3% and 86.4% respectively. Group with typical morphology consists of predominant AML with and without maturation, with high median blast count of 80% (range 57-96%), while only 2 patients had morphological dysplastic features. On the contrary, in group of patients without specific nuclear morphology and with NPM1 mutation, most of patients have dominant morphological dysplasia (21/33) or monoblastic appearance (7/33), with lower median blast count (51%, range 24-80%) Summary/Conclusion: Careful observation of nuclear morphology in AML patients enables early prediction of NPM1 status with high sensitivity, positive predictive value and accuracy.Keywords: Gene mutation, Mutation status, Cytogenetic abnormalities, Acute myeloid leukemia